Double "open and Shut" Transformation of γ-Carbolines Triggered by Ammonium Salts: One-Pot Synthesis of Multiheterocyclic Compounds

Article abstract of DOI:10.1021/acs.orglett.8b00332

A novel cascade reaction of indole-2,3-epoxide equivalents with γ-carbolines by utilizing a double "open and shut" transformation to access multiheterocyclic compounds containing both isotryptamines and pyrimido[1,6-a]indoles has been developed. This strategy utilizes the in situ formation of a bulky quaternary ammonium salt via ammonium exchange, which undergoes Hofmann elimination/vinylogous Mannich/retro-Mannich/cyclization cascade sequences.

Full text of DOI:10.1021/acs.orglett.8b00332

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Double “Open and Shut” Transformation of γ‑Carbolines Triggered
by Ammonium Salts: One-Pot Synthesis of Multiheterocyclic
Compounds
Takumi Abe,* Haruka Shimizu, Shiori Takada, Takahiro Tanaka, Mai Yoshikawa, and Koji Yamada*
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-tobetsu, Hokkaido 0610293, Japan
S
* Supporting Information
ABSTRACT: A novel cascade reaction of indole-2,3-epoxide
equivalents with γ-carbolines by utilizing a double “open and
shut” transformation to access multiheterocyclic compounds
containing both isotryptamines and pyrimido[1,6-a]indoles
has been developed. This strategy utilizes the in situ formation
of a bulky quaternary ammonium salt via ammonium
exchange, which undergoes Hofmann elimination/vinylogous
Mannich/retro-Mannich/cyclization cascade sequences.
γ-Carbolines and pyrimido[1,6-a]indoles represent two im-
portant heterocycles due to their rich biological activities
(Figure 1).1 For instance, gevotroline1 is an atypical
Mannich-type reaction,8 Pd-catalyzed cyclocarbonylation,9
Ullmann N-arylation/oxidative C−H amination,10 diamina-
tion/oxidative cross-coupling/bicyclization,11 Pd-catalyzed
asymmetric dearomative cyclization,12 and the reaction of 2-
bromomethylazoles and isocyanides.13 Among these strategies,
the retro-Mannich/cyclization of γ-carbolines is thought to be
the most concise methodology for the synthesis of pyrimido-
[1,6-a]indoles.14 This reaction proceeds by initial halogenation
of the γ-carboline, which then undergoes retro-Mannich
fragmentation followed by recyclization to afford the pyrimido-
[1,6-a]indole (Scheme 1a).7a
On the other hand, tetrahydro-γ-carbolines are cyclic
analogues of gramines, and the reaction of their ammonium
salts with nucleophilic agents must therefore be accompanied
by Hofmann elimination with cleavage of the C−N bond, and a
vinylogous Mannich reaction of indolenine at the benzylic
position, to afford isotryptamines, which are difficult to obtain
by other methods (Scheme 1b).15 Despite these advances
(Scheme 1a,b), the electrophiles are only limited to electro-
philic halogens or halogenated alkyl agents. Thus, finding
alternative electrophiles for the reaction with γ-carbolines is
appealing. Furthermore, to the best of our knowledge, the
synthesis of multiheterocycles containing both isotryptamines
or pyrimido[1,6-a]indoles is still challenging.
Previously, we reported the bench-stable equivalent of
indole-2,3-epoxide, 2-hydroxyindoline-3-triethylammonium
bromide (HITAB, 1), which was found to be a convenient
reagent for the formal C3-electrophilic reactions of indoles with
nucleophiles.16 During the studies on 1, we envisaged a cascade
reaction between in situ generated indolenines derived from 1
and γ-carbolines 2 via a Hofmann elimination followed by
Figure 1. Biologically active γ-carbolines and pyrimido[1,6-a]indoles.
antipsychotic agent (Figure 1a). Dimebon2 is an antihistamine
drug that has been used in Russia since 1983, which has been
proven to be a potent neuroprotective agent for treating
Alzheimer’s disease. Moreover, tubastatin A, which acts as a
histone deacetylase inhibitor (HDAC6), is expected to find
application as an anti-Alzheimer drug in clinical settings.3
Among various representative pyrimido[1,6-a]indole alkaloids,
such as ( )-hinckdentine,4 variolins,5 and (−)-vernavosine,
variolin B is a potent CDK inhibitor, whereas a (−)-vernavo-
sine ethyl ether derivative is known to exert a relaxation effect
on the phenylephedrine-induced contraction in isolated rat
aortic rings with a half maximal effective concentration (EC50)
of 2.48 μM.6 Therefore, a number of approaches for the
synthesis of pyrimido[1,6-a]indoles have been developed.
These involve retro-Mannich/cyclization of γ-carbolines,7
Received: January 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00332
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Cascade Reactions of γ-Carbolines
Table 1. Optimization of Reaction Conditions
X
Y
base
temp
%
b
run (equiv) (equiv)
(Z, equiv)
solvent
hexane
(°C)
yield
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
80
80
80
80
80
80
80
80
80
70
93
81
35
68
7
benzene
toluene
CHCl3
MeCN
DMF
DMSO
THF
0
0
1,4-
dioxane
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1.0
1.0
1.0
1.0
1.0
1.0
2.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.5
2.5
2.5
2.5
2.5
2.5
1.0
2.0
1.5
1.1
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (1.5)
Et3N (0.5)
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
80
50
rt
95
56
13
73
31
10
27
82
56
41
62
53
70
20
14
76
0
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
iPr2NEt (2) AcOEt
TMEDA (2) AcOEt
pyridine (2) AcOEt
DMAP (2)
DBU (2)
AcOEt
AcOEt
vinylogous Mannich/retro-Mannich/cyclization triggered by
another γ-carbolines 2 to afford the multiheterocyclic
compounds 3 (Scheme 1c). Based on our ongoing research
into the synthesis of heterocycles17 and the aforementioned
reactivity of γ-carbolines (Scheme 1a,b), we herein report a
novel cascade sequence starting from indole 2,3-epoxide
equivalents as electrophiles and γ-carbolines as nucleophiles
that furnished difficult-to-access multiheterocyclic compounds.
Initially, we investigated the reaction of 2-hydroxyindoline-3-
ammonium bromide 1a (1.0 equiv) and γ-carboline 2a (2.5
equiv) using Et3N (2.0 equiv) as a base in hexane at 80 °C over
the course of 16 h (Table 1, run 1). To our delight, 70% yield
of the target compound 3aa was obtained. Encouraged by this
initial result, other solvents were also then investigated.
Replacement of hexane with benzene and toluene increased
the yields of 3aa to 93% and 81%, respectively (runs 2 and 3).
Other solvents, such as CHCl3, MeCN, and DMF, turned out
to be less efficient in this cascade reaction (runs 4−6), and no
reaction occurred in the case of DMSO, THF, and 1,4-dioxane
(runs 7−9). Notably, the highest yield was achieved when
AcOEt was used (run 10). Further optimization showed that a
high reaction temperature was necessary to obtain a high yield
(runs 11 and 12). Before further optimization, the impact of the
equivalence of the reagents on the conversion was evaluated.
The results show that 1.0 equiv of 1a, 2.5 equiv of 2a, and 2.0
equiv of Et3N produced good conversion (runs 13−19).
Because it was anticipated that the base might play an
important role in this transformation, other bases were
investigated to improve the reaction efficiency. Other organic
bases such as iPr2NEt, TMEDA, pyridine, DMAP, DBU, and
DABCO (2) AcOEt
K2CO3 (2) AcOEt
Cs2CO3 (2) AcOEt
NaOH (2) AcOEt
0
0
a
1a (X ×x 0.5 mmol), 2a (Y × 0.5 mmol), and base (Z × 0.5 mmol) in
solvent (20 mL). Isolated yields.
b
DABCO were less effective than Et3N (runs 20−25). When
inorganic bases such as K2CO3, Cs2CO3, and NaOH were used,
ammonium bromide 1a was decomposed under the reaction
conditions (runs 26−28).18
Having defined the optimal reaction conditions, the substrate
scope of this cascade reaction was next evaluated (Scheme 2).
The presence of electron-donating or -withdrawing groups at
the C-5 position of the indole ring on 1 led to the
corresponding products in excellent yields (3ba: 91% yield,
and 3ca: 94% yield). The substituents on the nitrogen at the
piperidine ring critically influenced the efficacy of this
transformation.
Replacement of the methyl group with a benzyl substituent at
the nitrogen of the piperidine ring compromised the reaction
efficiency, and a lower yield of 3 was obtained (3ab: 32% yield,
3bb: 66% yield and 3cb: 0% yield). In the case of 3ab and 3cb,
1a or 1c could be recovered in 54% and 73% yield, respectively.
This result suggests that the ammonium exchange reaction
would be slow due to the steric hindrance of the benzyl
substituent. Electron-donating groups (3ac: 76% yield and 3ad:
93% yield) and electron-withdrawing groups (3ae: 86% yield)
B
DOI: 10.1021/acs.orglett.8b00332
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ab
,
group at the C-6 position had an obvious negative effect on
the yield (3af: 43% yield). No product could be obtained when
7-chloro-γ-carboline was used (3ag). Further combinations
with substituted 1 and γ-carbolines 2 were also tolerated (3bc:
91% yield, 3be: 92% yield, and 3ce: 44% yield). This cascade
reaction could also be performed on a gram scale by treating 1a
and 2a with Et3N in AcOEt. As a result, 3aa was obtained in
90% yield (1.18 g), which was comparable to the yield of 3aa
on a smaller scale (95% yield, 315 mg). Given that the
straightforward synthesis of multiheterocyclic compounds
containing both pyrimido[1,6-a]indoles and isotryptamines is
unprecedented,19 the present protocol using 1 as an electro-
phile is synthetically useful.
Scheme 2. Substrate Scope
Based on the above results and the literature prece-
dents,7,14,20−24 a plausible reaction pathway for this cascade
sequence is depicted in Scheme 3. At first, the ammonium
Scheme 3. Plausible Reaction Pathway
exchange of 1a by 2a via the indole 2,3-epoxide 4 affords the
bulky ammonium salt 5 with the release of Et3N. Upon
Hofmann elimination assisted by Et3N, 5 is converted to the
indolenium salt 6,20 which may increase the electrophilicity of
the benzylic position of isotryptamine.21 The benzylic position
of 6 is then attacked by another 2a molecule to afford the C-3-
alkylated intermediate 7.22 Subsequently, the retro-Mannich
reaction occurred to afford 8.23 Finaly, the intramolecular
Mannich-type cyclization of 8 assisted by Et3N gives 3aa with
the release of HBr.24 Notably, the significance of this protocol
not only is due to its great potential for accessing a variety of
multiheterocyclic compounds containing indolines, isotrypt-
amines, and pyrimido[1,6-a]indoles but also represents the first
example in which double and different “open and shut”
transformations of γ-carbolines are realized in a one-pot
manner.
a
1 (0.5 mmol), 2 (1.25 mmol), and Et3N (1.0 mmol) in AcOEt (20
b
mL) Isolated yields.
at the C-5 position of the γ-carbolines both resulted in excellent
yields. However, γ-carboline with an electron-withdrawing
C
DOI: 10.1021/acs.orglett.8b00332
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) Zhang, J.; Wu, X.; Gao, Q.; Geng, X.; Zhao, P.; Wu, Y.-D.; Wu,
A. Org. Lett. 2017, 19, 408.
(12) Douki, K.; Ono, H.; Taniguchi, T.; Shimokawa, J.; Kitamura, M.;
Fukuyama, T. J. Am. Chem. Soc. 2016, 138, 14578.
(13) Mendiola, J.; Minguez, J. M.; Alvarez-Builla, J.; Vaquero, J. J.
Org. Lett. 2000, 2, 3253.
In summary, we developed a novel cascade reaction of an
indole-2,3-epoxide equivalent with γ-carbolines. The method
utilizes double “open and shut” transformations to access
multiheterocyclic compounds containing both isotryptamines
and pyrimido[1,6-a]indoles from simple starting materials in
good to excellent yields. The rapid construction of complex
molecules from simple precursors has driven the development
of numerous synthetic strategies.19,25 Further applications of
this cascade reaction to other multiheterocyclic compounds are
currently underway.
(14) For a review, see: Alekseyev, R. S.; Kurkin, A. V.; Yurovskaya, M.
A. Chem. Heterocycl. Compd. 2011, 46, 1169.
(15) (a) Sapi, J.; Greb
1992, 383. (b) Diker, K.; de Maindreville, M.; Lev
1995, 36, 3511. (c) Yurovskaya, M. A.; Rodionov, I. L. Chem.
Heterocycl. Compd. 1981, 17, 794. (d) Lizarzaburu, M. E.;
Shuttleworth, S. J. Tetrahedron Lett. 2004, 45, 4781.
́
ille, Y.; Laronze, J.-Y.; Lev
́
y, J. Synthesis 1992,
́
y, J. Tetrahedron Lett.
ASSOCIATED CONTENT
* Supporting Information
■
(16) Abe, T.; Suzuki, T.; Anada, M.; Matsunaga, S.; Yamada, K. Org.
Lett. 2017, 19, 4275.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00332.
(17) (a) Abe, T.; Ikeda, T.; Yanada, R.; Ishikura, M. Org. Lett. 2011,
13, 3356. (b) Abe, T.; Ikeda, T.; Yanada, R.; Ishikura, M. Eur. J. Org.
Chem. 2012, 2012, 5018. (c) Abe, T.; Nakamura, S.; Yanada, R.;
Choshi, T.; Hibino, S.; Ishikura, M. Org. Lett. 2013, 15, 3622. (d) Itoh,
T.; Abe, T.; Choshi, T.; Nishiyama, T.; Yanada, R.; Ishikura, M. Eur. J.
Org. Chem. 2016, 2016, 2290. (e) Abe, T.; Yamada, K. Org. Lett. 2016,
18, 6504. (f) Abe, T.; Yamada, K. J. Nat. Prod. 2017, 80, 241. (g) Abe,
T.; Kida, K.; Yamada, K. Chem. Commun. 2017, 53, 4362. (h) Abe, T.;
Haruyama, T.; Yamada, K. Synthesis 2017, 49, 4141. (i) Abe, T.;
Takahashi, Y.; Matsubara, Y.; Yamada, K. Org. Chem. Front. 2017, 4,
2124. (j) Abe, T.; Terasaki, M. Helv. Chim. Acta 2018, 101,
No. e1700284.
Synthesis procedures and spectral and characterization
1
data, including H and 13C NMR (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: abe-t@hoku-iryo-u.ac.jp.
*E-mail: kyamada@hoku-iryo-u.ac.jp.
(18) The quaternary ammonium salt eliminates the least substituted
ORCID
olefin and a tertiary amine: (a) Spettel, M.; Pollice, R.; Schnurch, M.
̈
Takumi Abe: 0000-0003-1729-1097
Koji Yamada: 0000-0002-5084-7571
Notes
Org. Lett. 2017, 19, 4287. (b) Brewster, J. H.; Eliel, E. L. Org. React.
1953, 7, 99.
(19) Multicomponent Reactions; Zhu, J., Bienayme,
Weinheim, 2005.
́
H.; Wiley-VCH:
The authors declare no competing financial interest.
(20) (a) Snyder, H. R.; Eliel, E. L. J. Am. Chem. Soc. 1948, 70, 1703.
(b) Baciocchi, E.; Schiroli, A. J. Chem. Soc. B 1968, 401.
(21) (a) Tamura, Y.; Morita, I.; Tsubouchi, H.; Ikeda, H.; Ikeda, M.
Heterocycles 1982, 17, 163. (b) Tamura, Y.; Tsubouchi, H.; Morita, I.;
Ikeda, H.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1983, 1, 1937.
(22) (a) Nagai, Y.; Irie, A.; Uno, H.; Minami, S. Chem. Pharm. Bull.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
No. 16K18849 (T.A.) through a Grant-in-Aid for Young
Scientists (B).
1979, 27, 1922. (b) de la Herran, G.; Segura, A.; Csaky, A. G. Org. Lett.
́
́
̈
2007, 9, 961. (c) Nishimura, T.; Yamada, K.; Takebe, T.; Yokoshima,
S.; Fukuyama, T. Org. Lett. 2008, 10, 2601. (d) Li, S.-G.; Zard, S. Z.
Org. Lett. 2013, 15, 5898.
REFERENCES
■
(1) (a) Abou-Gharbia, M.; Patel, U.; Webb, M.; Moyer, J.; Andree,
T.; Muth, E. J. Med. Chem. 1987, 30, 1818. For a review, see:
(b) Abou-Gharbia, M. J. Med. Chem. 2009, 52, 2.
(23) (a) Ebnother, E.; Niklaus, P.; Suess, R. Helv. Chim. Acta 1969,
̈
̈
52, 629. (b) Cattanach, C. J.; Cohen, A.; Heath-Brown, B. J. Chem. Soc.
C 1971, 359.
(2) Doody, R. S.; Gavrilova, S. I.; Sano, M.; Thomas, R. G.; Aisen, P.
S.; Bachurin, S. O.; Seely, L.; Hung, D. Lancet 2008, 372, 207.
(3) (a) Butler, K. V.; Kalin, J.; Brochier, C.; Vistoli, G.; Langley, B.;
Kozikowski, A. P. J. Am. Chem. Soc. 2010, 132, 10842. (b) Kalin, J. H.;
Butler, K. V.; Akimova, T.; Hancock, W. W.; Kozikowski, A. P. J. Med.
Chem. 2012, 55, 639.
́
(24) (a) Laronze, J.-Y.; Bascop, S.-I.; Sapi, J.; Levy, J. Heterocycles
1994, 38, 725. (b) Kuehne, M. E.; Bohnert, J. C.; Bornmann, W. G.;
Kirkemo, C. L.; Kuehne, S. E.; Seaton, P. J.; Zebovitz, T. C. J. Org.
Chem. 1985, 50, 919.
(25) Ross, S. P.; Hoye, T. R. Org. Lett. 2018, 20, 100.
(4) Blackman, A. J.; Hambley, T. W.; Picker, K.; Taylor, W. C.;
Thirasasana, N. Tetrahedron Lett. 1987, 28, 5561.
(5) (a) Perry, N. B.; Ettounati, L.; Litaudon, M.; Blunt, J. W.; Munro,
M. H. G. Tetrahedron 1994, 50, 3987. (b) Trimurtulu, G.; Faulkner, D.
J.; Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro, M. H.
G.; Jameson, G. B. Tetrahedron 1994, 50, 3993. (c) Simone, M.; Erba,
E.; Damia, G.; Vikhanskaya, F.; Di Francesco, A. M.; Riccardi, R.;
Bailly, C.; Cuevas, C.; Fernandez Sousa-Faro, J. M.; D’Incalci, M. Eur.
J. Cancer 2005, 41, 2366.
(6) Nge, C.-E.; Gan, C.-Y.; Lim, K.-H.; Ting, K.-N.; Low, Y.-Y.; Kam,
T.-S. Org. Lett. 2014, 16, 6330.
(7) (a) Bhandari, K. S.; Snieckus, V. Synthesis 1971, 1971, 327.
(b) Hershenson, F. M.; Swenton, L.; Prodan, K. A. Tetrahedron Lett.
1980, 21, 2617.
(8) Higuchi, K.; Sato, Y.; Tsuchimochi, M.; Sugiura, K.; Hatori, M.;
Kawasaki, T. Org. Lett. 2009, 11, 197.
(9) Battistuzzi, G.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L. M.
Org. Lett. 2002, 4, 1355.
(10) Sang, P.; Xie, Y.; Zou, J.; Zhang, Y. Org. Lett. 2012, 14, 3894.
D
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